JPS61238781A - Novel intermediate and manufacture - Google Patents
Novel intermediate and manufactureInfo
- Publication number
- JPS61238781A JPS61238781A JP61083981A JP8398186A JPS61238781A JP S61238781 A JPS61238781 A JP S61238781A JP 61083981 A JP61083981 A JP 61083981A JP 8398186 A JP8398186 A JP 8398186A JP S61238781 A JPS61238781 A JP S61238781A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- optionally substituted
- substituted phenyl
- compound represented
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
〔発明の目的〕
産業上の利用分野
本発明は特定の一ンズアゼビン類の製造における中間体
として有用なピペラジン誘導体及びそのような中間体の
製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION INDUSTRIAL APPLICATION The present invention relates to piperazine derivatives useful as intermediates in the production of certain nzazebins and to processes for the production of such intermediates.
従来の技術
本出願人らによる共に係属中の欧州特許出頭公告第０１
３４９８４号は一般式（４）
（式中、Ｒは置換されていてもよいフェニル。PRIOR ART Co-pending European Patent Publication No. 01 by Applicants
No. 34984 has the general formula (4) (wherein R is optionally substituted phenyl.
Ｃｌ−８シクロアルキル＊ ｃｇ−ｓ シクロアルケ
ニル。Cl-8 cycloalkyl* cg-s cycloalkenyl.
直鎖または分枝状ＣＩ−，ブー。ル、直鎖または分枝状
Ｃ２−８アルケニル、５または６員へテロシクリルまた
は置換されていてもよいフェニルＣ１−４アルキルであ
リ ｙ／及び２の各々は同一または異なっていてもよく
、酸素または硫黄であり、そしてＸ′は−Ｃ迅−ま念は
酸素である〕で表わされる化金物及びとのような化合物
の製造方法を開示している。Straight chain or branched CI-, Boo. each of y/ and 2 may be the same or different, and each of y/ and 2 may be the same or different; or sulfur, and X' is -C--oxygen.
欧州特許出原公告第０１３４９８４号はまな一般式（式
中％ Ｘ’は式（Ａ）Ｋおけると同一の意義を有し、そ
してＲ１は水素、保護基または基 −Ｃ−ＲＣ式中、Ｒ
及びＹ′は成因におけると同一の意義を有する）である
）で表わされる化合物を開示しており、これらは式（４
）で表わされる化合物の製造の中間体として有用である
。European Patent Publication No. 0134984 Hamana general formula (where %X' has the same meaning as in formula (A)K, and R1 is hydrogen, a protecting group or a group -C-RC,
and Y' have the same meaning as in the composition), which are represented by the formula (4
) is useful as an intermediate for the production of compounds represented by
発明が解決しようとする問題点
本発明において、特定な一群の式の）で表わされる化合
物が対応するベンズアゼピン類の製造の中間体に特に有
用であることが見出された。Problems to be Solved by the Invention In the present invention, it has been found that a particular group of compounds of the formula ) are particularly useful as intermediates in the production of the corresponding benzazepines.
問題点を解決するための手段
従って、本発明は式（１）
（式中％ Ｒ” は置換されていてもよいフェニルま念
はＣｌ−８シクロアルキル＋ Ｃｌ−８シクロアルケ
ニル、ピラニルまたはチオピラニルであシ、そしてＸは
−Ｃ迅−または酸素である）で表わされる化合物を提供
する。Means for Solving the Problems Accordingly, the present invention provides a compound of the formula (1) (wherein %R" is optionally substituted phenyl, Cl-8 cycloalkyl + Cl-8 cycloalkenyl, pyranyl or thiopyranyl) and X is -C- or oxygen).
作用
Ｒ２が置換されていてもよいフェニルであるとき、それ
はハロゲン、Ｃ１−・アルキル、Ｃ□−アルコキシ、ニ
トロ、アミン、モノまたはジＣ１−＠アルキルアミノ及
びとドロキシから選択された１種以上の置換基により置
換されていてもよい。When R2 is optionally substituted phenyl, it is one or more phenyl groups selected from halogen, C1-alkyl, C□-alkoxy, nitro, amine, mono- or di-C1-@alkylamino and and-droxy. It may be substituted with a substituent.
好ましいｃｍ−ｓシクロアルキル基はシクロヘキシルで
ある。A preferred cm-s cycloalkyl group is cyclohexyl.
特に好ましい観点において、本発明は４−（シクロヘキ
シルカルボニル）−１−（３−フェニルプロピル）ピー
ラジン−２，６−ジオンを提供する０
別の観点において、本発明は上で定義した式（１）で表
わされる化合物の製造方法を提供し、この方法は
ａ）式［［）
（式中、Ｒ”は式（１）におけると同一の意義を有する
）で表わされる化合物またはその塩を式（ＩＩＩ）Ｃｌ
烏−Ｘ−ＣＣ迅）、 −Ｒｊ （１）（式
中、Ｒｓは離脱基であり、そしてｘＦｉ式（１）におけ
る同一の意義を有する）で表わされる化合物と反応させ
るか、または
ｂ）式（ＩＶ）
Ｒ２ＣＯ・Ｙ （ＩＶ）（式中％
Ｒ”は式（Ｉ）におけると同一の意義を有し、そしてＹ
は離脱基である）で表わされる化合物を１−（３−フェ
ニルプロピル）ピペラジン−２゜６−ジオンと反応させ
る
ことを含む。In a particularly preferred aspect, the invention provides 4-(cyclohexylcarbonyl)-1-(3-phenylpropyl)pyrazine-2,6-dione. In another aspect, the invention provides a compound of formula (1) as defined above. Provided is a method for producing a compound represented by a) formula [[] (wherein R'' has the same meaning as in formula (1)) or a salt thereof; )Cl
(1) (wherein Rs is a leaving group and has the same meaning in xFi formula (1)), or b) (IV) R2CO・Y (IV) (% in the formula
R'' has the same meaning as in formula (I), and Y
is a leaving group) with 1-(3-phenylpropyl)piperazine-2°6-dione.
好適には、Ｒ３は臭素もしくはヨウ素原子ま念はトシレ
ート基、好ましくはヨウ素原子である。Suitably, R3 is a bromine or iodine atom, preferably a tosylate group, preferably an iodine atom.
好適には、Ｙはハロゲン原子である。Preferably, Y is a halogen atom.
好ましくは、Ｙは塩素原子である。Preferably, Y is a chlorine atom.
好適には、式（ＩＩＩ）で表わされる化合物は式（Ｉｆ
）で表わされる化合物のアルカリ金属塩、好ましくはカ
リウムまたはナトリウム塩と反応させる。Preferably, the compound of formula (III) is of formula (If
) with an alkali metal salt, preferably a potassium or sodium salt.
好適には、式（Ｉｆ）で表わされる化合物のアルカリ金
属塩は式（Ｉｆ）で表わされる化合物を、好ましくは微
細化した、炭酸カリウムのようなアルカリ金属塩と反応
させることにより現場生成させる。水素化ナトリフΔ全
規模用途に使用できる。Preferably, the alkali metal salt of the compound of formula (If) is formed in situ by reacting the compound of formula (If) with an alkali metal salt, preferably finely divided, such as potassium carbonate. Hydrogenated Natrif Delta can be used in all scale applications.
好適には、式■及び（ＩＩ）の化合物間の反応は非プロ
トン性溶媒１例えばジメチルホルムアミド中で完結まで
周囲温度ないし加熱温度で、３０〜１２０℃の温度範囲
で、好ましくは７０℃ないし１１０℃で行なわれる。Suitably, the reaction between the compounds of formula (II) is carried out in an aprotic solvent such as dimethylformamide at ambient to heated temperatures to completion in the temperature range from 30 to 120°C, preferably from 70°C to 110°C. It is carried out at ℃.
好適には、式ＣＰり及び１−（３−フェニルプロピル）
ピペラジン−２，６−ジオンの反応は不活性溶媒、例え
ばジクロルメタンまたはクロロホルム中で例えばトリエ
チルアミンのような好適な塩基の存在下で任意の好便な
温度、例えば０〜５℃で行なわれる。Preferably, formula CP and 1-(3-phenylpropyl)
The reaction of piperazine-2,6-dione is carried out in an inert solvent such as dichloromethane or chloroform in the presence of a suitable base such as triethylamine at any convenient temperature, e.g. from 0 to 5<0>C.
反応は薄層クロマトグラフィーのような通常の技術によ
り監視される。完結後、必要な生成物は単離されかつ調
製用クロマトグラフィーのような通常の方法により精製
される。The reaction is monitored by conventional techniques such as thin layer chromatography. After completion, the required product is isolated and purified by conventional methods such as preparative chromatography.
本発明の中間体化合物は次いで欧州特許出願公告第０１
３４９８４号中の類似により開示され六方法により一般
式囚で表わされる化合物に転換されうる０
更に詳しくは、本発明は式（ト）
個
Ｃ：Ｏ（ｙ）
（式中％ Ｒ”及びＸは式（１）におけると同一の意義
を有する）で表わされる化合物の製造方法を提供し。The intermediate compounds of the present invention can then be used in European Patent Application Publication No. 01
34984, which can be converted into a compound of the general formula by a method disclosed by analogy in No. 34984. Provided is a method for producing a compound represented by the formula (having the same meaning as in formula (1)).
この方法は式（Ｉ）で表わされる化合物を閉環すること
を含む。This method involves ring-closing a compound of formula (I).
ｒ（１）で表わされる化合物は酸触媒による処理により
閉環でき、好便には濃硫酸のような酸が使用され、仁の
場合、反応は低温で、例えば−１０’Ｃ〜４０℃で、好
ましくは２５℃未満、特＆ＣＯ〜５℃で行なわれる。The compound represented by r(1) can be ring-closed by treatment with an acid catalyst, conveniently an acid such as concentrated sulfuric acid is used, and in the case of sulfur, the reaction is carried out at a low temperature, e.g. Preferably it is carried out at a temperature below 25°C, especially at a temperature of ~5°C.
好適には、式（Ｉ）で表わされる化合物は酸触媒への添
加の前に最少量の不活性溶媒、例えばジクロルメタン、
または特にクロロホルムに溶解される。Preferably, the compound of formula (I) is added to the acid catalyst with a minimum amount of an inert solvent, such as dichloromethane,
or especially dissolved in chloroform.
実施例
以下、実施例により本発明を説明するが、本発明はこれ
ら＃Ｃ限定さｔ、るものではない。EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these #C.
参考例 ■
１−（３−フェニルプロピルコピペラジン−２゜６−ジ
オン
１−（３−フェニルフロビル）−４−ベンジルピペラジ
ン−２，６−ジオン（３，０ｆ）ｔ−酢酸（８０ｍｌ）
及び水（８就〕の混合物に溶解し念溶液ｔ−４５℃で大
気圧下でパラジウム担持木炭触媒（Ｏ８６５ｆ）の存在
下３時間水添した。混合物をセライトで一過し、溶媒を
真空下で除去し、残漬ｆ５チ塩酸水溶液に溶解しな。こ
の溶液をクロロホルムで洗浄し、固体炭酸す） ＩＪウ
ムの添加により塩基性化し、クロロホルムで抽出し、抽
出物を乾燥させた（ＭｇＳＯ＋）。溶媒の蒸発により表
題化合物を白色固体１．９ｆ（８８％）として得大。Reference example ■ 1-(3-phenylpropylcopiperazine-2゜6-dione 1-(3-phenylfurovir)-4-benzylpiperazine-2,6-dione (3,0f) t-acetic acid (80ml)
and water (8 parts) and hydrogenated at -45°C under atmospheric pressure for 3 hours in the presence of palladium on charcoal catalyst (O865f).The mixture was passed through Celite and the solvent was evaporated under vacuum. The remaining F5 was removed by dihydrochloric acid and dissolved in aqueous solution of hydrochloric acid. The solution was washed with chloroform and solid carbonate was basified by the addition of IJium, extracted with chloroform and the extract was dried (MgSO+). . Evaporation of the solvent gave the title compound as a white solid, 1.9f (88%).
実施例１
４−（シクロヘキシルカルボニル）−１−（３−フェニ
ルフロビル）ピペラジン−２，ｓ−１オン微細化した炭
酸カリウム（１１，４０Ｋｆ、 ８２．５ｍｏｌｅ）
ｋ ４− （シクロヘキシルカルボニルコピペラジン−
２，６−ジオン（６，１６７Ｋｇ、 ２７．５ｍｏｌｅ
）のジメチルホルムアミド（３３，５ｄｍり中攪拌溶液
に周囲温度で添加し、攪拌混合物を６０〜６５℃に１時
間加熱した。ｌ−ブロム−３−フェニルプロパ７Ｃ５，
４７５Ｋｇ、４１８ ｄｍ’、 ２７．５ｍｏｌｅ）及
びヨウ化カリウム（４，９３Ｋｆ、 ２９．７ｍｏｌｅ
） ｋ添加し、得られた混合物を唆拌し、９８〜１０
０℃で４５分間加熱した。Example 1 4-(cyclohexylcarbonyl)-1-(3-phenylfurovir)piperazine-2,s-1 micronized potassium carbonate (11,40 Kf, 82.5 mole)
k 4- (cyclohexylcarbonylcopiperazine-
2,6-dione (6,167Kg, 27.5mole
) was added to a stirred solution of dimethylformamide (33.5 dm) at ambient temperature and the stirred mixture was heated to 60-65° C. for 1 hour. l-bromo-3-phenylpropa 7C5,
475Kg, 418 dm', 27.5mole) and potassium iodide (4,93Kf, 29.7mole
) k and stirred the resulting mixture, 98-10
Heated at 0°C for 45 minutes.
混合物を２０℃に冷却し、水（ｉ２３ｄｍ’）を添加し
、次いで混合物を酢酸エチル（２Ｘ７２ｄｍ”）で抽出
した。抽出物を合せ、水洗しく２Ｘ９８ｄｍす、硫酸マ
グネシウムで乾燥させたっｆ通抜、溶液に低容積（約ｆ
２ｄｍ”）の蒸発により、白色生成物を沈殿はせ、これ
ｆｔ濾過により集めた。The mixture was cooled to 20° C., water (i23dm') was added and the mixture was then extracted with ethyl acetate (2X72dm''). The extracts were combined, washed with water 2X98dm, dried over magnesium sulfate and drained. Add a small volume to the solution (approximately f
Evaporation of 2 dm'') precipitated a white product, which was collected by ft filtration.
物質の第二の収穫金、Ｐ液の蒸発及び得られ六面体の酢
酸インプロピルエチルの粉末化により単離した。A second crop of material was isolated by evaporation of the P solution and powdering of the resulting hexahedral impropylethyl acetate.
総収量 ７．７６Ｋｆ（８２，４チ〕融点８９℃実施例
２
４−（シクロヘキシルカルボニル）−１−（３−フェニ
ルプロピル）ピペラジン−２，６−ジオン塩化シクロヘ
キサノイル（１，２Ｐ）ｉ０’Ｃで保持Ｌｆｌ−（３−
フェニルフロビル）ピペラジン−２，６−ジオン（１，
８５ｌ ）のクロロホルムＣ７０ｍＬ、エタノール不含
）中溶液に添加し、トリエチルアミン（１，０２ｔ）ｔ
−添加した。混合物ｔ−ｏ℃で３０分間、次いで室温で
１６時間保持した。溶液を希塩酸、飽和炭酸水素ナトリ
ウム及び水で順次洗浄した。溶液を乾燥させ（ＭｇＳＯ
＋ ）、蒸発させることにより表題化合物を白色固体２
．７１（１００チ）として得た。Total yield 7.76 Kf (82,4%) Melting point 89°C Example 2 4-(Cyclohexylcarbonyl)-1-(3-phenylpropyl)piperazine-2,6-dione Cyclohexanoyl chloride (1,2P) i0' Lfl-(3-
phenylfurovir) piperazine-2,6-dione (1,
Triethylamine (1,02 t) was added to a solution of
- Added. The mixture was kept at t-o<0>C for 30 minutes and then at room temperature for 16 hours. The solution was washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate and water. Dry the solution (MgSO
+ ), the title compound was obtained as a white solid by evaporation 2
．． 71 (100chi).
実施例３及び４は中間体４−（シクロヘキシルカルボニ
ル）−１−（３−フェニルフロビル）ヒヘラシンー２．
６−シオンカラの２−（シクロヘキシルカルボニル）−
４−オキノー１．２．３．４゜６、 ７． ８． １２
ｂ−オクタヒドロピラジノ〔２，１−ａ ） （２）ベ
ンズアゼピンの製造を示している。Examples 3 and 4 are intermediates 4-(cyclohexylcarbonyl)-1-(3-phenylfurovir)hiheracin-2.
6-Shionkara 2-(cyclohexylcarbonyl)-
4-Okino 1.2.3.4゜6, 7. 8. 12
b-octahydropyrazino[2,1-a) (2) Shows the production of benzazepine.
実施例３
４−（シクロヘキシルカルボニル） −１−（３−フェ
ニルプロピル）−６−ヒトロキシピペラジンー２−オン
実施例１からのピペラジンジオン（４、ｓＫ４．１４．
０２ｍｏｌｅ） ｆジクロルメタン（１４、ｌｄｍ”）
に溶解し、エタ／ −ｋ （８４，４ｄｍ’） ｔ−添
加し、溶液′ｔ−０ｔＫ冷却した０塩化銅Ｑ［）二水和
物（２，６２９紛、１５．４２ｍｏｌｅ）のエタノ−ｋ
（８，５ｄｍり中溶液を添加し、得られ次溶液を０℃
で１時間攪拌しｆｃ。Example 3 4-(Cyclohexylcarbonyl)-1-(3-phenylpropyl)-6-hydroxypiperazin-2-one Piperazinedione (4, sK4.14.
02mole) f dichloromethane (14, ldm”)
Copper chloride Q[) dihydrate (2,629 powder, 15.42 mole) was dissolved in ethano-k (84,4 dm') and the solution was cooled.
(8.5 dm of medium solution was added, and the resulting solution was heated to 0°C.
Stir for 1 hour at fc.
次いで、ホウ水素化ナトリウム（２，６５１Ｋｔ、 ７
０．１ｍｏ ｌ ｅ ）を１時間かけて強攪拌下で少量
ずつ添加した。添加中、温度は約０℃に保持したが、あ
る一時点にておびただしい気体発生を伴って１０℃に上
昇した。添加完結後、暗色混合物ｆｔＯ℃で１．５時間
攪拌した。Next, sodium borohydride (2,651Kt, 7
0.1 mol) was added little by little over 1 hour with strong stirring. During the addition, the temperature was kept at about 0°C, but at one point rose to 10°C with copious gas evolution. After the addition was complete, the dark mixture was stirred at ftO 0 C for 1.5 hours.
メタノール（７，６ｄｍりを添加し、混合物を３０分間
１２℃まで加熱しながら攪拌した◆次いで、水（３０５
ｄｍ”）Ｑ慎重に添加し、次いでジクロルメタン（５５
ｄｍ”） ｆ添加した０セライトでを洗浄し、層分離し
、水性相をジクロルメタン（ｌＸ５５ｄｍ”、ＩＸ４０
ｄｍ”）で抽出し念。Methanol (7.6 dm) was added and the mixture was stirred while heating to 12°C for 30 min.
dm") Q carefully and then dichloromethane (55
dm'') was washed with added 0 celite, the layers were separated and the aqueous phase was dissolved in dichloromethane (1X55dm'', IX40
dm”)).
有機抽出物を合せ、飽和塩化す） ＩＪウム溶液（６５
ｄｍりで洗浄し、乾燥させ（Ｍｇ５ｏ、 ）、次いで濾
過の後、蒸発させることにより無色油状物質を得た。こ
れを温（３０℃）イングロビルアルコール（４，５ｄｍ
ａ）に溶解し、温（５０℃）イングロビルエーテル（４
５ｄｍ”）ｉ添加することによシ４．１３Ｋｆ（８５，
５％）の生成物を白色固体、融点１１１℃として沈殿ぐ
せた。Combine the organic extracts and saturated chloride) IJum solution (65%
A colorless oil was obtained by washing with DM, drying (Mg5o, ), then filtration and evaporation. Add this to warm (30°C) inglovil alcohol (4.5 dm
Inglovir ether (4
By adding 5dm”)i, 4.13Kf (85,
5%) of the product was precipitated as a white solid, melting point 111°C.
実施例４
２−（シクロヘキシルカルボニル）−４−オキソ−１，
２，３，４，６，７，８，１２ｂ−オクタヒドロピラジ
ノ−（２，ｌ −ＩＬ 〕（２）ベンズアゼピン実施例
３からのヒドロキシピペラジン（４，０３Ｋｔ、１１．
７ｍｏｌｅ）のりａｏホルム（６，ｌ ｄｍり中溶液を
１時間要して攪拌中の濃硫酸（２２ｄｍ３）に０℃で添
加し大。得られた溶液を０℃で２時間攪拌し、次いで温
度を５℃未満に保持した砕氷（約１５０ｄｍりにゆっく
り慎重に注加しな。クロロホルム（２０ｄｍ’）ｉ添加
し、層分離し、水性層をクロロホルム（２Ｘ１６ｄｍっ
て抽出した。有機抽出物を合せ、過剰の飽和炭酸水素ナ
トリクム溶液（２８ｄｍ’）及び飽和塩化ナトリウム溶
液（２８ｄｍって洗浄し、乾燥させ（ＭｇＳＯ＋）、蒸
発させることにより白色固体を得た。酢酸エチル（３３
ｄｍ’ ）及びエタノール（１０ｄｍりから熱濾過を伴
って再結晶することによって精製することにより表題化
合物の２回分の収穫が得られた。収量合計３．２４Ｋｔ
（８４，８％）、融点１８９℃。Example 4 2-(cyclohexylcarbonyl)-4-oxo-1,
2,3,4,6,7,8,12b-octahydropyrazino-(2,l-IL)] (2) Benzazepine Hydroxypiperazine from Example 3 (4,03Kt, 11.
A solution of 7 moles of glue in aoform (6,1 dm) was added to stirring concentrated sulfuric acid (22 dm3) at 0°C over a period of 1 hour.The resulting solution was stirred at 0°C for 2 hours, then the temperature was increased. Add slowly and carefully to crushed ice (approximately 150 dm) kept below 5°C. Chloroform (20 dm') was added, the layers were separated, and the aqueous layer was extracted with chloroform (2 x 16 dm). The organic extracts were combined. , washed with excess saturated sodium bicarbonate solution (28 dm') and saturated sodium chloride solution (28 dm'), dried (MgSO+) and evaporated to give a white solid. Ethyl acetate (33
Purification by recrystallization with hot filtration from ethanol (10 dm') and ethanol (10 dm) yielded two crops of the title compound. Total yield 3.24 Kt.
(84.8%), melting point 189°C.
代理人 弁理士 秋 沢 政 光 他 １ 名Agent Patent Attorney Masaaki Akizawa 1 other person
Claims (9)
Ｃ＿３＿−＿８シクロアルキル、Ｃ＿５＿−＿８シクロ
アルケニル、ピラニルまたはチオピラニルであり、そし
てＸは−ＣＨ＿２−または酸素である）で表わされる化
合物。(1) Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^2 is optionally substituted phenyl, C_3_-_8 cycloalkyl, C_5_-_8 cycloalkenyl, pyranyl or thiopyranyl, and X is -CH_2- or oxygen).
き、これはハロゲン、Ｃ＿１＿−＿６アルキル、Ｃ＿１
＿−＿６アルコキシ、ニトロ、アミノ、モノ−またはジ
−Ｃ＿１＿−＿６アルキルアミノ及びヒドロキシから選
択された１種以上の置換基により置換されている特許請
求の範囲第（１）項記載の化合物。(2) When R^2 is optionally substituted phenyl, this represents halogen, C_1_-_6 alkyl, C_1
The compound according to claim (1), which is substituted with one or more substituents selected from ____6 alkoxy, nitro, amino, mono- or di-C_1_-_6 alkylamino and hydroxy.
（１）項記載の化合物。(3) The compound according to claim (1), wherein R^2 is cyclohexyl.
フェニルプロピル）ピペラジン−２，６−ジオンである
特許請求の範囲第（１）項記載の化合物。(4) 4-(cyclohexylcarbonyl)-1-(3-
The compound according to claim (1), which is phenylpropyl)piperazine-2,6-dione.
Ｃ＿３＿−＿８シクロアルキル、Ｃ＿５＿−＿６シクロ
アルケニル、ピラニルまたはチオピラニルである）で表
わされる化合物またはその塩を式（III）Ｃ＿６Ｈ＿５
−Ｘ−（ＣＨ＿２）＿２−Ｒ＾３（III）（式中、Ｒ＾
３は離脱基であり、そしてＸは−ＣＨ＿２−または酸素
である） で表わされる化合物と反応させることを特徴とする特許
請求の範囲第（１）項記載の式（ I ）で表わされる化
合物を製造する方法。(5) Formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^2 is optionally substituted phenyl, C_3_-_8 cycloalkyl, C_5_-_6 cycloalkenyl, pyranyl, or thiopyranyl) or a salt thereof is represented by the formula (III)C_6H_5
-X-(CH_2)_2-R^3(III) (in the formula, R^
3 is a leaving group, and X is -CH_2- or oxygen). How to manufacture.
される化合物のアルカリ金属塩と反応させる特許請求の
範囲第（５）項記載の方法。(6) The method according to claim (5), wherein the compound represented by formula (III) is reacted with an alkali metal salt of the compound represented by formula (II).
Ｃ＿３＿−＿８シクロアルキル、Ｃ＿５＿−＿８シクロ
アルケニル、ピラニルまたはチオピラニルであり、そし
てＹは離脱基である）で表わされる化合物を１−（３−
フェニルプロピル）ピペラジン−２，６−ジオンと反応
させることを特徴とする特許請求の範囲第（１）項記載
の式（ I ）で表わされる化合物を製造する方法。(7) Formula (IV) R^2CO・Y(IV) (wherein R^2 is optionally substituted phenyl or C_3_-_8 cycloalkyl, C_5_-_8 cycloalkenyl, pyranyl or thiopyranyl, and Y is a leaving group)
A method for producing a compound represented by formula (I) according to claim (1), which comprises reacting with phenylpropyl)piperazine-2,6-dione.
わされる化合物を閉環することを特徴とする式（Ｖ）▲
数式、化学式、表等があります▼（Ｖ） （式中、Ｒ＾２は置換されていてもよいフェニルまたは
Ｃ＿３＿−＿８シクロアルキル、Ｃ＿５＿−＿８シクロ
アルケニル、ピラニルまたはチオピラニルであり、そし
てＸは−ＣＨ＿２−または酸素である）で表わされる化
合物を製造する方法。(8) Formula (V) ▲ characterized by ring-closing the compound represented by formula (I) described in claim (1)
There are mathematical formulas, chemical formulas, tables, etc.▼(V) (wherein R^2 is optionally substituted phenyl or C_3_-_8 cycloalkyl, C_5_-_8 cycloalkenyl, pyranyl or thiopyranyl, and X is - A method for producing a compound represented by CH_2- or oxygen.
ヘキシルである特許請求の範囲第（８）項記載の方法。(9) The method according to claim (8), wherein X is -CH_2- and R^2 is cyclohexyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8509435 | 1985-04-12 | ||
| GB858509435A GB8509435D0 (en) | 1985-04-12 | 1985-04-12 | Intermediates & process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61238781A true JPS61238781A (en) | 1986-10-24 |
Family
ID=10577550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61083981A Pending JPS61238781A (en) | 1985-04-12 | 1986-04-11 | Novel intermediate and manufacture |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0199485B1 (en) |
| JP (1) | JPS61238781A (en) |
| DE (1) | DE3682221D1 (en) |
| ES (1) | ES8801641A1 (en) |
| GB (1) | GB8509435D0 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4889848A (en) * | 1984-11-06 | 1989-12-26 | Hoffmann-La Roche Inc. | Tricyclic pyridine derivatives |
| ZW17385A1 (en) * | 1984-11-06 | 1986-02-19 | Hoffmann La Roche | Tricyclic pyridine derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134984A1 (en) * | 1983-07-16 | 1985-03-27 | Beecham Group Plc | Benzazepine and benzoxazepine derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2520740A1 (en) * | 1982-01-29 | 1983-08-05 | Sanofi Sa | PROCESS FOR THE PREPARATION OF ACYL-2-HEXAHYDRO-1,3,4,6,7,11B-2H-PYRAZINO (2,1-A) ISOQUINOLEINONES-4 AND INTERMEDIATES |
-
1985
- 1985-04-12 GB GB858509435A patent/GB8509435D0/en active Pending
-
1986
- 1986-04-07 DE DE8686302548T patent/DE3682221D1/en not_active Expired - Lifetime
- 1986-04-07 EP EP19860302548 patent/EP0199485B1/en not_active Expired
- 1986-04-10 ES ES553875A patent/ES8801641A1/en not_active Expired
- 1986-04-11 JP JP61083981A patent/JPS61238781A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134984A1 (en) * | 1983-07-16 | 1985-03-27 | Beecham Group Plc | Benzazepine and benzoxazepine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ES8801641A1 (en) | 1988-02-16 |
| EP0199485A3 (en) | 1987-09-02 |
| EP0199485B1 (en) | 1991-10-30 |
| EP0199485A2 (en) | 1986-10-29 |
| ES553875A0 (en) | 1988-02-16 |
| DE3682221D1 (en) | 1991-12-05 |
| GB8509435D0 (en) | 1985-05-15 |
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